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Author Kiwamoto, R. ♦ Spenkelink, A. ♦ Rietjens, I. M. C. M. ♦ Punt, A.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ACROLEIN ♦ ALKYLATION ♦ DETOXIFICATION ♦ DISEASES ♦ DNA ADDUCTS ♦ FOOD ♦ FOOD ADDITIVES ♦ GLUTATHIONE ♦ IN VITRO ♦ IN VIVO ♦ INCUBATION ♦ INTAKE ♦ NADP ♦ RISK ASSESSMENT ♦ SIMULATION ♦ TOXICITY
Abstract Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-01-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 282
Issue Number 1


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